New compound could alleviate side effects of antidepressant drugs

Researchers have discovered a new substance via screening that they say could resolve the problems of ‘tricyclic antidepressants’. 

Some severe depressions may be treated with tricyclic antidepressants, which are more effective than therapies for mild and moderate conditions. However, this class of drugs are inducing significantly more and more serious side effects. 

Now, scientists from the Faculty of Health and Medical Sciences at the University of Copenhagen, Denmark, in collaboration with Lundbeck A/S, UK, and the National Institutes of Health in Baltimore, US, have discovered a compound that may solve this issue.

“We have discovered a substance, Lu AF60097, that works in a different way from the ones presently in use. If the new substance works, it may help the existing drugs get rid of the serious side effects,” said Professor Claus Juul Løland at the Department of Neuroscience at the Faculty of Health and Medical Sciences. 

Løland explained that blocking the return transport of serotonin requires a relatively large dose of antidepressant substance. When this is with tricyclic antidepressants, serious side effects can occur, including life-threatening heart problems to severely dry mouth, visual disorders, development of mania, weight problems and digestive challenges.

The researchers have screened a number of substances from Lundbeck’s drug library to find one that had a sufficiently strong link to the ‘allosteric site’. This is the location where the substance binds to another site on the serotonin transporter (SERT). 

When a substance binds to the allosteric site rather than the same site as serotonin, it is possible to regulate the function of the serotonin transporter instead of completely blocking it, say the researchers. The researchers identified Lu AF60097 as this molecule and tested its efficacy and safety in cells and rat models. 

“In this case, we have shown that when we bind this substance to the allosteric site while giving the tricyclic antidepressant, we can amplify the binding of the antidepressant substance. Therefore, we can use a much smaller concentration of the antidepressant substance. It might cause fewer side effects, but have the same therapeutic effect,” said Løland. “We have taken the first step, but perhaps also the biggest. We have shown that the concept works. If it also works in practice, hopefully in the future it can be used to treat people with severe depression.”

The findings were published in Nature Communications.